Homocysteine, a revolutionary look at arteriosclerosis (Pt. 2)

No disease has been investigated more thoroughly and painstakingly than arteriosclerosis, not even cancer. For the longest time, the cholesterol/fat interpretation was the only explanation available. With the work of Dr. McCully, new evidence showed a different view of the disease that revolutionized this field of medicine. One of his major contributions can be summarized as follows:

“The idea that plaques are filled with only greasy fat deposits is incorrect for the vast majority of plaques. Many arteriosclerotic plaques even in advanced disease are of the fibrous and fibrocalcific type that are found in subjects with homocystinuria. Typically, arteriosclerotic plaques are tough, inelastic, thickened and heavily encrusted with calcium deposits, making them difficult to dissect with scalpel or scissors. In advanced plaques, their complex structure also includes cholesterol crystals, fatty deposits, areas of degeneration or death of tissue, blood clots, protein deposits, the growth of small blood vessels into the artery wall and areas of bleeding that predispose the sufferer to a complete blockage by formation of blood clots“.

Dr. McCully did not seek to dispose of the cholesterol theory. He felt that the many years of research on the theory could be integrated into his new discoveries. For this reason, he honored the work of other researchers in the cholesterol field by asserting:

“Experts in the development of plaques agree that lipoproteins do participate in the early stages of plaque formation by forming foam cells. Adherents of the cholesterol/fat hypothesis correctly point out that elevated cholesterol levels are associated with increased risk of arteriosclerosis.”

But association is not cause, therefore he saw many shortcomings in the traditional view of the disease and he sought to find answers. In his autopsy study of almost 200 veterans, for instance, the group with the most severe disease had a mean cholesterol of 16 and 2/3 had no evidence of diabetes, high blood pressure or elevated cholesterol. The defenders of the cholesterol theory claim that even if cholesterol is low, it must cause the disease because of the correlation of risk with elevated levels. The homocysteine theory can explain arteriosclerosis even with low levels of cholesterol.

Dr. McCully recognized the challenge that treating the disease had become and this prompted him to assert:

“When treating manifestations of arteriosclerosis, heart attack, stroke, kidney failure or gangrene of feet and legs, the medical profession frequently encounters the disease in its late stages, when decades of gradual narrowing of coronary, carotid renal or iliac arteries by arteriosclerosis have occurred silently before symptoms occur. In attempting to treat serious disease late in its course, difficult problems are encountered by physicians and surgeons. Drug therapy to lower cholesterol may be ineffective and complicated by toxic side effects and by failure to respond, mainly because the disease is so far advanced. Efforts to stop the progress of arteriosclerosis by controlling blood cholesterol and lipoproteins through dietary modification and drug therapy are difficult. And changing lifetime habits of poor diet and nutritional abuse are usually ineffective in the elderly. Some practitioners in the arteriosclerosis field because of their training have neglected nutritional and preventive measures to treat advanced disease and have been reluctant to accept the new approach. Nutritional scientists, on the contrary, have just recently began to concentrate on the role of partial vitamin deficiencies and imbalances in degenerative diseases.”

A new era in cardiovascular testing

When Dr. McCully did his research, the homocysteine theory had not been widely accepted and it was just beginning to be re-examined by increasing numbers of medical investigators worldwide. A reliable test for blood homocysteine levels had just began to be applied to human studies. Dr. McCully saw the need to plan and conclude long-term prospective trials to test the homocysteine theory of arteriosclerosis. He also called for the need to have some funding which for decades, he said, had been “lavished on the cholesterol/fat hypothesis”. He saw the need for clinical tests to document changes in blood homocysteine, levels of vitamins B 6, folic acid, B 12, LDL, HDL and tests of major organ function. He also saw the need to document the clinical complications of arteriosclerosis such as heart attack, stroke, gangrene and embolism to be established by reliable criteria. Several decades later, his desire might have come true.

Today a test for homocysteine can be obtained from independent laboratories and most alternative medicine doctors are on board with it. Dr. David Jockers, asserts that “lipid panels are archaic and scientists have demonstrated that these tests have many limitations and only identify 40% of those at risk for coronary heart disease.” He asserts “People drop dead everyday with “normal” cholesterol levels, “normal” blood pressure and “normal” EKG findings. Scientists have found much more advanced blood tests that can far more accurately assess your risk of heart disease.” These kinds of tests have opened “a new era of cardiovascular testing” (1)

In his article titled ‘What are your homocysteine levels?’ Dr. Jockers explains that “The best way to test homocysteine levels is through a combination lab that looks at other factors involved in cardiovascular health.” One of these tests is C-Reactive Protein, which looks at inflammation levels in the body and is a much better way of assessing cardiovascular risk than total cholesterol. Also the Lp(a) and the VAP test. The Vertical Auto Profile Test (VAP) test “identifies twice as many people at risk than routine cholesterol tests, including those with inherited risk factors who often develop premature heart disease. It measures total cholesterol, HDL (“good” cholesterol), LDL (“bad” cholesterol), and triglycerides. The VAP Test also measures cholesterol subclasses that play important roles in the development of heart disease.” (2)

Similarly, Dr. Whitaker, in his article ‘Nutrient spotlight: Benefits of B vitamins’ mentions how deficiencies of the B vitamins can elevate homocysteine levels, among other things. (3) Dr. Stephen Sinatra, in his article ‘Heart risk factor: homocysteine’ explains how homocysteine can be a risk factor for heart disease. (4)

How can you protect yourself from the damaging effects of homocysteine?

According to the author, arteriosclerosis is a disease which begins in childhood and adolescence, develops gradually without symptoms during the early adult years and affects men often suddenly in their 40’s, 50’s and 60’s.  Because of the silent, gradual, and prolonged onset of arteriosclerosis, the most successful strategy for prevention must start in childhood and continue in adolescence and adulthood, providing the elder years with little risk of developing heart attack, angina pectoris, stroke, kidney failure or peripheral vascular disease. This lifelong strategy requires control of known modifiable risk factors, especially consumption of an optimal diet, moderate physical activity and avoidance of tobacco, drugs and alcohol.

Dr. McCully’s research yielded enough information to make prevention of the disease within our reach. The best way to carry out this preventive strategy is outlined in the rest of this article. In this sense, one of the most appealing features of the homocysteine theory is its simplicity and ease of application in its prevention, even though from a scientific point of view the theory is complex in many ways. Anybody can understand the basic principles of the theory and do something about it. He suggests prevention should emphasize limitation of methionine consumption and augmentation of natural sources of B 6, B 12 and folic acid. Prevention and treatment with supplemental vitamins must be at sufficient doses to ensure control of blood homocysteine. Other factors affecting homocysteine levels, such as age, gender, family history, thyroid function, kidney function, blood pressure, diabetes, drugs, hormones and toxins must also be taken into consideration.

A person at risk has to understand this: homocysteine is derived from methionine, a normal amino acid building block of all proteins in the diet. This amino acid can damage the artery walls if allowed to accumulate excessively in the body’s blood and tissues. The other important aspect to understand is that the level of homocysteine in the blood is controlled by the action of three B vitamins- B 6, B 12 and folic acid- within the body. Consumption of these vitamins on a daily basis can protect against the development of homocysteine for a lifetime. In a disease of aging like arteriosclerosis some risk factors can be modified, others cannot (age, gender, genetics). Attention to all of the contributing factors will guarantee protection from the disease. The blood homocysteine level ideally should be kept on the 8 to 10 micromole per liter range to be protected from the progression of the disease. Dietary and lifestyle changes can accomplish this. Even in the case of genetic predisposition to the disease, increasing the consumption of B 6, B 12 and folic acid can keep homocysteine levels from building up in the blood. Despite the known fact that individuals require different amounts of vitamins and minerals for optimal health according to their genetic makeup, gender, etc. These measures are best coordinated with physicians and surgeons who specialize in the treatment of established vascular disease.

Dietary prevention of arteriosclerosis

In its simplest form, an optimal diet to prevent arteriosclerosis consists of abundant fresh vegetables and fruits, whole grains and legumes, limited quantities of fresh meat and dairy products, a minimum of highly processed and packaged foods and strictly limited consumption of fats and sugars. Unfortunately, the typical American diet of fast convenient foods is the major cause for the high risk of arteriosclerosis and its complications of coronary heart disease, stroke, kidney failure and generalized vascular disease in the U.S.

Because of persuasive evidence that dietary deficiency of folic acid in pregnant women leads to birth defects in newborn infants, especially neural tube defects such as spina bifida, the FDA ruled back in 1998 that sufficient folic acid be added to enriched foods to ensure that a minimum intake of 400 mcg of folic acid per day for pregnant women. The amounts of dietary folic acid and vitamin B 6 that are required to prevent abnormal elevation of blood homocysteine are 350 to 400 mcg per day of folic acid and 3 to 3.5 mg per day of vitamin B 6.

Vitamin B 12

Unlike B 6 and folic acid which are found in foods of animal and plant origin, B 12 is formed only by bacteria, fungi and algae. Yeast, plants and animals cannot make it and they depend on microorganisms to obtain B 12. When we consume these animal foods we can obtain B 12. When it comes to absorption, a protein made in the stomach called ‘intrinsic factor’ helps B 12 be absorbed. Additional protein factors in the blood are required for transport of vitamin B 12 to the liver and other organs. Eating a diet of animal products will provide 5 mcg per day of B 12, vs the 3 mcg established by the RDA.

Absorption of B 12 is impaired by inflammation of the stomach, ulcer disease typical of the elderly, etc. In conditions like pernicious anemia, because of lack of intrinsic factor required for absorption, there is no absorption of B 12. In this case injections of B 12 are necessary to avoid pernicious anemia and neurological damage to the spinal cord. Strict vegetarians can develop pernicious anemia after 20-30 years. In subjects with low levels of vitamin B 12 in the blood homocysteine becomes elevated (13-15 micromoles per liter) Elevations of homocysteine and B 12 are so related that hematologists use this as an indicator of inadequate B 12 absorption or inadequate dietary folic acid intake.


Of all the 20 amino acids, homocysteine is derived only from methionine. All proteins contain methionine, but animal foods like meat, eggs, milk and cheese contain more methionine than plant foods, 2 to 3 times more. Plant foods on the contrary contain larger amounts of B 6 and folic acid. The key to understanding homocysteine for animal food eaters is that the more these foods are consumed, the higher the intake of B 6 and folic acid has to be. Processing, cooking and storing foods causes loses of these vitamins, which can lead to elevations of homocysteine.

Fresh meats, liver and eggs, if not excessively processed, heated or preserved, contain abundant amounts of vitamin B 12, B 6 and folic acid. On the contrary, cooked or baked foods that contain cane or beet sugar, corn syrup or fruit sugars are highly processed carbohydrates that contain no vitamins or minerals. A diet that is 25-30 % sugar and contains 40-50% calories from fats, forces the body to obtain its dietary requirement for B vitamins from the remaining 25-30% of food calories. Consequently, this diet can lead to deficiencies of the B vitamins.

Processed foods

Food processing, milling, heating, chemical additives, radiation and storage can lead to up to 85-90%  loss of B vitamins. Raw ingredients that are frozen will only lose 10-15%. A highly processed diet, together with high consumption of fats and sugars will lead to elevation of homocysteine, arterial damage and arteriosclerosis over a period of months and years. The brain has appetite control centers capable of producing eating behavior sufficient to supply the body with vitamins and minerals adequate with survival. This means that a diet that is high in fats and sugars and therefore deficient in crucial vitamins and minerals will force the body to eat more in order to obtain these vital nutrients. This will lead to obesity and diabetes, which will accelerate the development of arteriosclerosis.


Fiber is the indigestible starch-like roughage of plants. It can be soluble (fruit pectins) or insoluble (vegetable lignins and celluloses). In either case,  fiber is not digested or absorbed into the bloodstream, but stays in the stomach, intestine and colon during digestion of food. Therefore, it fills the stomach, producing satiety and increases the intestinal contents promoting regular elimination. It has no calories or nutritional value but the fiber of plants is rich in vitamins and minerals. Studies have shown an inverse relation between consumption of dietary fiber and many major diseases like arteriosclerosis.

Vitamin E and other antioxidants

Numerous studies have shown that vitamin E can reduce arteriosclerosis and coronary heart disease up to 50%.


Magnesium is essential for the action of enzymes that process proteins and the amino acids methionine and homocysteine. Zinc is also important for numerous functions of the body, including expressions of DNA and the aging process. These and other minerals are seriously depleted when whole grains are refined (up to 50-90%). Chromium, copper, manganese, selenium and molybdenum are required for optimal health. Fresh meats, seafood, and fresh vegetables will ensure adequate intake of these elements. Iodine is also important to make thyroid hormone, deficiencies in this vital mineral will cause goiter, elevation of blood homocysteine, increased blood cholesterol and lipoproteins and therefore susceptibility to coronary heart disease. The ‘Heart and Body Extract’ is formulated with kelp as one of its ingredients. Kelp is a rich source of iodine as well as other nutrients and is renown for its powerful nutritional benefits.

According to the research of Dr. Jockers, “Kelp is extraordinarily rich in alkaline buffering nutrients such as sodium, potassium, magnesium and calcium. It is also a phenomenal source of chlorophyll that boosts blood cell formation and purifies the body”. According to him, “kelp is considered the world’s most potent source of naturally occurring iodine”, it assists in blood sugar control because of its vanadium content, helps with poor digestion, supports the prostate, rebuilds and maintains all glands in the body, detoxifies the body of heavy metals and radiation and heals the liver, among other things. Kelp is also a wonderful source of a “unique group of polysaccharides called fucoidans” which have been shown to reduce pain, fight viruses and prevent arteriosclerosis. These sulfated polysaccharides “are also revered for their powerful ability to reduce blood clots” (5)


Dr. McCully emphasized how the B vitamins are key to the prevention of arteriosclerosis. He singled out three key B vitamins, namely B 6, B 12 and folic acid. Since the B vitamins work together as a complex, it would be a good idea in my opinion to take the whole B complex together. The ‘Female Balance Extract‘ contains other key B vitamins therefore it is a good complement to the homocysteine protocol. The ‘Ginseng Extract‘ is also a perfect complement to the B complex.

Other dietary factors

Other trace compounds in the diet are known to lower homocysteine levels. These compounds are found in foods like beets, garlic and onion. The sulfur compounds in these foods are also beneficial in lowering homocysteine levels in the blood. The ‘Heart an Body Extract’ contains garlic, which in combination with other herbs, makes a wonderful complement to the homocysteine diet proposed by Dr. McCully. Like kelp, garlic is considered a superfood herb, it is anti-inflammatory and one of nature’s powerful antibiotics. According to the research of Dr. Jockers “garlic is also used to lower blood pressure, cholesterol and help prevent/reverse cancer” (6)

Other foods like omega 3 unsaturated fish oil and plant oils are also helpful in lowering homocysteine levels. Apart from this, fish oil is a good source of B 6.

Oxycholesterols, the products of reaction of highly purified cholesterol with oxygen rapidly cause arteriosclerotic plaques as shown in animal experiments. The highly damaging oxycholesterols are found in foods in which cholesterol is subjected to heating and exposure to the oxygen of air during food processing, cooking and preservation. Examples are dried egg yolk, milk powder and fried foods. The oxycholesterols of these foods are absorbed into the blood stream during digestion where they become concentrated in the LDL fraction of the plasma causing damage to arterial wall cells and tissues promoting arteriosclerosis.

Optimal diet for health

The most important prerequisites for health are quality, freshness, variety and balance. Fresh means the food has been minimally processed and consumed quickly after harvesting if possible. B 6 is available abundantly in fresh vegetables, meats and fish. Folic acid is abundant in dark leafy vegetables and in liver. Vitamin B 12 is needed in extremely low amounts and is available only in foods of animal origin such as meat, eggs, fish and dairy products. Vegetables should be eaten with the peel and cooked with minimum heat as the B vitamins are sensitive to loss through heating, 6-10 servings a day is optimal. 2 to 4 oz of meat, poultry, fish or eggs provide more than adequate animal protein in a single day. Flavor can be provided by herbs, spices and oils like olive oil.

Animal foods need not be consumed everyday. For those who want to avoid meat, a serving of several ounces of eggs, milk or cheese several times per week will provide adequate B 12 to prevent anemia and a buildup of homocysteine in the blood. Vegans who do not consume animal products of any kind need to supplement their diets with 0.1 mg vitamin B 12 per day or 1 mg intramuscular injection per month to prevent deficiency of this important vitamin. Avoidance of pastries, cakes, heavy fried foods, sugary foods of all kinds will constitute a major improvement in overall health.

Selecting the best processed foods

The main purpose of processed foods is to increase storage potential, however major losses of vitamins occur. Examples are flour from whole grains, sugar from sugar beets, cane or corn, oils from olives or grains, etc. In the case of flour, almost 90% of the vitamins are lost. With beets, cane or corn, the final product is pure sucrose with none of the vitamins present in the original product. Separation of olive oil from olives removes virtually all of the water soluble vitamins, minerals and fiber with the exception of cold pressed olive oil which keeps the antioxidants.

Cholesterol is protected in the body against the oxygen of air by an elaborate combination of antioxidant vitamins, minerals and enzymes. When cholesterol of animal foods is exposed to the oxygen of air by food processing highly damaging cholesterol oxides are formed This is the case of powdered egg yolks, highly used in processed foods.

Canning foods require heating food and cans are sealed hot to exclude as much air as possible, this affects two important vitamins B 6 and folic acid as much as 35%.

Lifestyle factors and homocysteine levels


Non smokers have lower levels of homocysteine than smokers. Cigarette smoke contains over 60 different toxic substances besides carbon monoxide.

Drugs and toxins

Some chemotherapy drugs, antiepileptic and antihypertensive drugs have been found to increase blood homocysteine levels because they antagonize the action of folic acid or B 6 in the body.


There are no doubts of the benefits of moderate exercise for overall health and to lower the levels of homocysteine. Vigorous exercise, however, may cause heart attack in an individual with arteriosclerosis and coronary heart disease because of nutritional, genetic or lifestyle history.


The fully oxidized form of homocysteine has been demonstrated to be a very potent exciter of brain function. Some children with high levels of homocysteine have been observed to have increased risk of convulsions and patients with fibromyalgia/chronic fatigue syndrome have highly elevated levels of homocysteine in cerebrospinal fluid. This may suggest that elevated homocysteine may modify behavior to produce stressful personality traits or neuropsychiatric disorders.

Alcohol use

People who abuse alcohol have been shown to have elevated blood homocysteine levels. Alcohol intake leads to serious depletion of body stores of folic acid. There are numerous examples of severe arteriosclerosis with stroke, coronary heart disease, kidney failure and peripheral vascular disease in alcoholics. Moderate consumption of alcohol however, 12 drinks per day, depending on body weight has long been known to increase longevity.

Heavy consumption of coffee, more than 9 cups a day, was associated with some elevation of homocysteine. While tea had the opposite effect.

Genetic background, sex hormones and aging

Genetics accounts for 1/3 of the cases of coronary heart disease. One important cause of this predisposition is an abnormal inherited form of methylene-tetra-hydrofolate reductase  which affects around 5% of the population in the homozygous form (when both parents are carriers of the gene) and 38% of  the French Canadian population in the heterozygous form. An individual from a family that carries this mutation requires more folic acid in the diet or from supplements than somebody without this defect. Dr. McCully recommends 1,000 mcg per day in this case. 50 % of cases of homozygous homocystinuria respond to large doses of B 6. Any individual with a family history either in ancestors or descendants would be advised to consume a lifelong supplement of 125 mg per day of B 6. A family history of arteriosclerosis and heart disease implies a major contribution of genetic factors in causation.

Several medical conditions that may be determined genetically to some degree have a major effect on the risk of arteriosclerosis and coronary heart disease. These are diabetes, hypertension, high levels of blood cholesterol or lipoprotein(a) and decreased thyroid function. Excessive, intensive medical therapy is usually required to control these medical conditions, favorably decreasing the risk of heart disease.

High cholesterol

Individuals with a significant elevated level of total blood cholesterol and LDL have an increased risk of cardiovascular disease. The treatment of this condition with diet, drugs, hormones and exercise has proven unsuccessful and dangerous when you consider the unpleasant side effects on muscle optic lens and carcinogenic effects. The effects of supplementation with B 6, folic acid and B 12 in lowering homocysteine, cholesterol and LDL was demonstrated in a small number of patients with elevated cholesterol levels, although the effect on vascular disease risk has not been determined. Theoretically, a significant decrease in the homocysteine content of LDL by this strategy should be beneficial because the strategy also decreases the formation of LDL aggregates containing homocysteine.


Elevation of homocysteine and arteriosclerosis is correlated with aging in both men and women. Because of decreased intake of nutrients and poorer absorption  and mastication by the elderly, it is recommended that B vitamins be given as a supplement in this amount: 10 mg of vitamin B 6, 1.0 mg of folic acid, and 0.1 mg of vitamin B 12 per day may help minimize the risk in homocysteine levels.

Prevention of arteriosclerosis

Many clinical studies have shown the effectiveness that dietary improvements and supplemental B 6, folic acid and vitamin B 12 have in lowering homocysteine. A diet  with fewer processed foods that contained adequate levels of B vitamins was effective in lowering blood homocysteine levels. A multicenter European study with 75 vascular cases and 800 controls showed that consumption of B 6, folic acid or B 12 reduced the risk of vascular disease by approximately two thirds.

The homocysteine revolution: medicine for the new millennium

What began as a chance observation in children with rare inherited diseases of homocysteine metabolism started a promising new field of medical research with the potential to unlock mysteries that had long puzzled medical scientists.

Since the discovery of homocysteine in the 70’s by Dr. McCully, a lot of new information has shed light in the understanding of the role that this seemingly unimportant byproduct of protein breakdown, homocysteine, could have in living cells and tissues, degenerative diseases of cancer and arteriosclerosis. This new field of research also opened up new understanding of how vital nutrients like vitamins A, C, B 12, B 2, folic acid, E and B 6 function within cells and tissues to control the basic processes of life itself: cellular respiration, cell and tissue growth, cell removal and replacement, maintenance of connective tissues, expression of genetic information, reproduction and embryonic development.

A large number of human studies  have confirmed the validity of the homocysteine approach to arteriosclerosis, which has caused the causes to be rewritten. The simplicity of the homocysteine theory has led to new proposals for the control of the disease with promising strategies for the successful treatment of cardiovascular disease.

Anybody can assure adequate dietary intake of vitamins, minerals, fiber, antioxidants and other beneficial nutrients to prevent or delay the onset of homocysteine. The different studies on the disease explain the supreme importance of lifelong consumption  of an optimal diet combined with cessation of smoking, adequate exercise and other simple measures. This strategy for prevention of arteriosclerosis is revolutionary because  it shifts the emphasis toward consumption of beneficial nutrients and places the consumption of fats and sugars in a new context, emphasizing that depletion of essential nutrients is the key factor in understanding the origin of disease. Rather than seeing the disease as caused by excess consumption of cholesterol and fats, homocysteine sees arteriosclerosis as a deficiency disease. Several discoveries by medical scientists in biochemistry, physiology and oncology are showing how the homocysteine theory is helping us understand cancer and the aging process as well as arteriosclerosis.

In conclusion, the research of Dr. McCully provided a powerful breakthrough in the understanding of degenerative diseases like arteriosclerosis. Thanks to his work, we have a great tool to take our health in our own hands. All the products at ‘Healthy Heart Club’ are a great addition to your health protocol.

Thanks for reading.


(1) http://drjockers.com/cardiopower-testing/

(2) http://drjockers.com/homocysteine-levels/

(3) http://www.drwhitaker.com/nutrient-spotlight-benefits-of-b-vitamins/

(4) http://www.drsinatra.com/heart-risk-factor-homocysteine/

(5) http://drjockers.com/6-major-health-benefits-of-sea-kelp/

(6) http://drjockers.com/the-immune-boosting-power-of-garlic/

Homocysteine, a revolutionary look at arteriosclerosis (Pt. 1)

Dr. Kilmer S. McCully is credited with one of the major medical and scientific breakthroughs of this century. A graduate of both Harvard College and Harvard Medical school, in 1968 he opened a new field of medicine when he discovered homocysteine, a breakdown of dietary protein with many potential health risk factors.  His research opened a new pathway of medical research that relates homocysteine to arteriosclerosis, cancer, aging, normal growth and development and the degenerative diseases of aging.

His accomplishments are many and worth noting: at Harvard University, he studied cholesterol biosynthesis and pregnenolone metabolism. He was appointed Research Associate in Biochemistry at National Institutes of Health, where he studied tRNA structure. In 1963 he won an American Cancer Society Faculty Research. He studied amino acid metabolism in the laboratory of James Watson, the discoverer of the DNA structure. During 1965-1968, he served as Clinical and Research Fellow in Pathology at Massachusetts General Hospital. During which, he studied protein synthesis in organ cultures of human tumors.

Following his residency in pathology, Dr. McCully began his study of homocysteine and vascular disease in 1968 in the Pathology Department at Massachusetts General Hospital. He won a Career Development Award from the National Institutes of Health from. He was appointed Associate Pathologist at Massachusetts General Hospital and Assistant Professor of Pathology at Harvard Medical School and the Harvard-Massachusetts Institute of Technology Program in Health Sciences and Technology. After leaving Harvard in 1979, he was appointed Visiting Professor of Laboratory Medicine at the University of Connecticut. In 1981 he was appointed Pathologist at the Veterans Affairs Medical Center in Providence and Associate Professor of Pathology at Brown University. He is currently Chief of Pathology and Laboratory Medicine, Director of the Boston Area Consolidated Laboratories at the Veterans Affairs Medical Center in West Roxbury, Massachusetts, and Medical Director of the Network Consolidated Laboratories for Veterans Affairs Medical Centers in New England. He also serves as Associate Clinical Professor of Pathology at Harvard Medical School.

During his tenure at the Veterans Affairs Medical Centers in Providence and Boston, Dr. McCully continued his studies of homocysteine metabolism in arteriosclerosis, cancer and degenerative diseases. He has published over 80 research articles in peer-reviewed journals in his field of investigation from 1961 until 2012. He has also published two monographs, several book chapters, and several reviews in medical journals, two books for the general reader and a book of his scientific memoirs. He currently holds seven U.S. Patents for anti-neoplastic and anti-atherogenic derivatives of homocysteine thiolactone.

In 1998 Dr. McCully was given the Linus Pauling Functional Medicine Award by the Institute for Functional Medicine and the Norman E. Clarke, Sr. Award by the American College for Advancement in Medicine. In 1999 he was given the Burton Kallman Scientific Achievement Award by the National Nutritional Foods Association and the Kynett Foundation Cardiology Award of Excellence by the College of Physicians of Philadelphia. In 2000 he received the International Integrative Medicine Award by the International Journal of Integrative Medicine, the Dinsdale Award by the Society for Scientific Exploration, the Benjamin Franklin Literary and Medical Society Award, and the Lifetime Achievement Award in Clinical Nutrition by the International and American Associations of Clinical Nutritionists. In 2000 Dr. McCully was honored by citation to the Twentieth Century Hall of Fame by Prevention Magazine. In 2001 he was given the Gallery of Heroes Award by Men’s Journal Magazine. Also in 2001 he was given a Commendation by the Veterans Affairs Medical Center in Providence. In 2003 he was awarded the Integrity in Science Award of the Weston A. Price Foundation and the Edward Rhodes Stitt Award in Laboratory Medicine by the Association of Military Surgeons of the United States. His biography is currently listed in Marquis Who’s Who in America. (1)

In his first book, ‘The homocysteine revolution’, Dr. McCully details his research on homocysteine, opening a new understanding to the underlying cause and prevention of heart disease. Based on his findings, he proposes dietary and lifetime changes the reader can easily implement. In what follows we will look at his homocysteine theory and how it applies to heart disease and arteriosclerosis.

We will also see how all the products from the ‘Healthy Hearts Club’ are the perfect complement to the homocysteine diet.

The mysterious case of stroke in childhood

It all started in 1968. After finishing his many years of education in chemistry, medicine, biochemistry, molecular biology, genetics and pathology, Dr. McCully was given a research laboratory at Massachusetts General Hospital in Boston. While working with the human genetics unit at the hospital, and after examining many patients with genetic diseases, he was presented with the case of a 8-year-old who, 35 years earlier, had died of a disease of old age. The official cause of death was ‘arteriosclerosis of the carotid artery with cerebral infarct (hardening of the artery leading to the brain with death of brain tissue)’. The boy’s obscure case had been published in the November 23 issue of the ‘New England Journal of Medicine’ in 1933 and forgotten. Thirty-two years later, the boy’s nine-year-old niece, presented the same symptoms as her uncle. Studying the chemical composition of her urine, doctors found it contained homocysteine, an amino acid derived from the normal breakdown of proteins in the body. She was diagnosed with homocystinuria and the doctors concluded her uncle must have died of the same disease.

Dr. McCully had never heard of this disease, it had been discovered 6 years earlier by medical investigators in Belfast, Ireland. By that time, two more cases had been discovered in the U.S. A physician named Dr. Harvey Mudd had studied several more cases and he had discovered that in this disease the liver is unable to dispose of homocysteine normally because of a genetic error in a liver enzyme called cystathionine synthase. Another doctor, George Spaeth and his associates, found that vitamin B 6 lowered the amount of homocysteine found in the urine. The liver enzyme that Dr. Mudd had discovered to be abnormal in homocystinuria needs B 6 for normal activity. This enzyme converts homocysteine into cystathionine, which is further processed in the liver to cysteine and finally excreted in the urine.

Dr. McCully recovered the tissues from the original slides and re-studied the case from 1933. He found the walls of the carotid arteries leading to the brain were severely thickened and damaged by arteriosclerosis. Blood clots prevented blood from reaching the brain of the child causing death of the right half of the brain. He also found scattered, widespread changes in all the small arteries of the body similar to those he found in many elderly patients. There was no cholesterol deposited in the walls of the child’s arteries, which prompted many questions. Was this hardening of the arteries caused by homocysteine? Was there an effect on cholesterol and fat? Why was there no cholesterol in the walls of the child’s arteries? Was this disease in children the same arteriosclerosis found in the elderly?

Other doctors in Belfast and London had studied ten cases of children affected by this disease. Many of these children had died from blood clots in the brain, heart and kidneys, hardening of the arteries resulting from fibrous plaques and loss of elasticity. All these cases were identical to the 8-year-old-boy case in 1933. It was not clear yet how homocysteine could produce changes in the arteries resembling arteriosclerosis without affecting cholesterol, lipoproteins or fats in the blood and artery walls.

Some time later, Dr. McCully found another case of homocysteine, this time in a 2-month-old baby. In addition to homocysteine, this baby had another substance related to the disease called cystathionine and a different liver enzyme being affected. This enzyme was found to be unable to transform homocysteine into methionine using B 12, which in a normal liver is performed quickly and easily. The enzyme that was found to be abnormal in the other cases was normal in the 2 month-old baby, but this baby had the same arteriosclerosis as the other children. Dr. McCully studied the organs of the diseased baby and comparing all the cases, he found that in all these rare genetic cases, the amino acid homocysteine had caused damage and hardening of the arteries by a direct effect on the cells and tissues lining the arteries.

He was so excited about his discovery, he could hardly sleep for two weeks. If homocysteine causes damage to the arteries, what could this mean for the general population with heart disease? When Dr. McCully was studying these cases (1950-60’s), heart disease was already an epidemic in America and the prevailing theory was that high cholesterol depositing in the walls of the arteries causes heart disease. He wanted to know how homocysteine could be related to high cholesterol and heart disease.

By reviewing research, he found two key discoveries that helped him understand homocysteine better. One was the work of Dr. James Rinehart, who had published a paper 20 years earlier where he discussed how a diet deficient in vitamin B 6 fed to monkeys led to arteriosclerotic changes in the arteries. The other was the findings of biochemists in Russia who discovered that the liver enzyme that converts homocysteine to cystathionine needs B 6 for its action. Could Rinehart’s monkeys with a B 6 deficiency have had a buildup of homocysteine that damaged their arteries? On the other hand, Dr. Harvey Mudd had found the enzyme cystathionine to be abnormal in children with homocystinuria. Another researcher, George Spaeth, had found that some children with this disease respond dramatically to large doses of B 6, preventing a buildup of homocysteine in their blood and urine. Dr. McCully was unable to explain how homocysteine related to cholesterol in causing damage to arteries because, in all cases, children with the disease had normal levels of cholesterol. The monkeys in Rinehart’s experiment also had normal levels of cholesterol.

While preparing his paper for publication, Dr. McCully read the work of some doctors from Toronto who had been working with choline, a component of lecithin. They found that a deficiency of choline in the diet of rats caused arteriosclerotic changes in the rats’ arteries and fat build up in the liver. This raised the possibility that arteriosclerosis was caused by a buildup of homocysteine in the rats’ blood.

With all these new findings, Dr. McCully published his paper stating that homocysteine damages the arteries by a direct effect on the arterial cells and tissues in homocystinuria caused by two different genetic defects. He also hypothesized that arteriosclerosis was caused by elevated blood homocysteine levels probably caused by vitamin B and choline deficiencies. His paper received hundreds of requests for reprints from scientists from all over the world.

Three different types of homocysteine

So far, Dr. McCully had found out that regardless of the cause, elevations of homocysteine causes arteriosclerosis by damaging the cells and tissues of the arteries. In this sense, a third type of homocystinuria confirmed his observations because they all had this element of damage regardless of the liver enzyme that was abnormal.

In type one, the most frequent case of the disease, B 6 was effective in preventing high levels of homocysteine. In type two, the next most frequent case, folic acid corrected the abnormality and lowered homocysteine. In type three, the rarest form of homocysteine, B 12 had little effect because of the difficulty of the liver to absorb this B vitamin.

The cholesterol theory vs. the homocysteine theory

As he continued with his publications and lectures, Dr. McCully encountered different reactions to his theories, but mostly skepticism. He believes due to the failure to find cholesterol in the patients. The explanation that an amino acid, not cholesterol, caused these cases of arteriosclerosis made it harder to accept.

But Dr. McCully was still trying to bring together the new research with the established knowledge. In the traditional view, excess fats and cholesterol are believed to damage the arteries. In the homocysteine theory, arteries are damaged by the effects of homocysteine on cells and tissues of arteries, leading to loss of elasticity, hardening, calcification, narrowing of the lumen and formation of blood clots inside arteries. It is an intoxification from proteins vs. an intoxification from fats. The homocysteine theory considers arteriosclerosis a result of an dietary imbalance due to the ingestion of protein and low levels of B vitamins, while the cholesterol theory considers the cause to be the ingestion of dietary fats.

Cholesterol in the body

Dr. McCully explains that cholesterol is “carefully controlled and adjusted according to the needs of the different organs of the body. If the amount of cholesterol is increased in the diet, a healthy well functioning liver makes less cholesterol for the needs of the body. If the amount of cholesterol in the diet is decreased, the liver makes more cholesterol.” In this way, the body regulates very precisely how much cholesterol is produced for its needs. Since it is so tightly regulated, Dr. McCully’s argument is, how could an excess of cholesterol induce arteriosclerosis?

He further explains that cholesterol is needed in the body for the production of sex hormones (estrogen and androgen), the production of stress and mineral hormones of the adrenal gland, it is a major constituent of the membranes of all cells of the body and it is excreted in the bile in the form of bile salts. According to Dr. McCully, there also needs to be an explanation on how cholesterol, a normal chemical constituent in the body, could, when overeaten in the diet, cause arteriosclerosis.

Cholesterol and oxidation

Early attempts to identify which components of LDL are injurious to artery walls led to the testing of many chemical relatives of cholesterol. A group of cholesterol compounds that contain extra oxygen atoms was found to be highly toxic when tested in cell cultures and in fragments of aorta maintained in culture. Several of these oxidized cholesterol compounds, called oxycholesterols, produced injury to artery walls, deposition of fat and arteriosclerotic plaques when fed to rabbits. One of the most toxic of these oxycholesterols is ‘cholestane triol’, which has three added oxygen atoms per cholesterol.

In a series of studies of oxycholesterols, medical scientists at Albany Medical College showed that purified cholesterol, freed from all traces of oxycholesterols and protected from the oxygen of air, does not produce arteriosclerosis when administered on animals.  These oxycholesterols have been discovered in arteriosclerotic plaques of human arteries and in the LDL fraction of human blood plasma coming from dietary fats of animal sources, specially those that have been heated in the presence of air.

Shortcomings of the cholesterol/fat approach

During the 80 years of its existence, the cholesterol/fat approach to arteriosclerosis became the favorite of the medical community. Because of his deep research on arteriosclerosis, Dr. McCully thinks the cholesterol/fat approach to arteriosclerosis has many shortcomings. One of the biggest ones according to him is that it fails to explain a correlation between fat and cholesterol and the major changes produced by arteriosclerosis. Especially taking into account that the fat and cholesterol content of the American diet has changed very little in the recent decades.

He also feels that it fails to consider the potent effects of the oxycholesterol contaminants found in feeding experiments with animals.

Furthermore, the author sees a major flaw with the cholesterol approach because a majority of people with severe or fatal arteriosclerosis, myocardial infarction, kidney failure or gangrene of the toes have normal cholesterol and lipoprotein levels. He even asserts: “At a practical level, physicians know that the majority of their patients with coronary heart disease have no incidence of elevated cholesterol or LDL levels”. He considers that in all of the very intensive clinical investigations done through the decades on cholesterol lowering drugs, there has not been a noticeable reduction in heart disease mortality and arteriosclerosis remains the leading cause of death in America.

What is more, he asserts that no comprehensive theory has been developed which satisfactorily explains how arteriosclerosis risk factors affect cholesterol levels or how elevated LDL and decreased HDL initiate formation of arteriosclerotic plaques.

To support his arguments, Dr. McCully did a research of 194 autopsy studies of male veterans with severe arteriosclerosis and found only 8% of them had high cholesterol, diabetes or hypertension. According to him, the cholesterol/fat approach has yet to provide a coherent scientific theory which explains how cholesterol, a normal constituent of the body, or excess dietary fat produces arteriosclerosis.

He also found that a diet abundant in vitamin E, a potent fat-soluble antioxidant vitamin, keeps LDL from being oxidized by oxygen, therefore it is of benefit in reducing the risk of coronary heart disease in both men and women.

Beyond cholesterol

Dr. McCully sees the need for a new, comprehensive and effective approach for prevention and treatment of arteriosclerosis, since it is still the leading cause of deaths in the US. He considers the discovery of homocystinuria in young children is a great opportunity to understand arteriosclerosis better.

The homocysteine theory of arteriosclerosis

The homocysteine theory is based on the results of animal experiments and the study of human subjects at risk of arteriosclerosis. In essence, it relates the underlying cause to a buildup of homocysteine in the blood caused by dietary, genetic, toxic, hormonal and aging factors. Specifically,  an imbalance between the methionine of dietary protein and the dietary intake of vitamins B 6, B 12 and folic acid needed to prevent accumulation in the cells and tissues of the body. The importance of this theory is that it explains many aspects of the disease that cannot be explained by the cholesterol/fat hypothesis. It also explains why the diet of developed countries accelerate its progression.

The dietary factors that determine high blood homocysteine levels are the total methionine content of dietary protein and the content of vitamins B 6, B 12 and folic acid in the diet. The only source of homocysteine in the body is from the methionine of dietary proteins: meats, seafood, dairy products, eggs, etc.

Methionine is an amino acid containing sulfur that is present in all proteins. It is an essential amino acid because all animals including man require it for proper growth and maintenance of all cells and tissues of the body. B 12 and folic acid help convert homocysteine to methionine. B 6 converts homocysteine to cystathionine, which in turn is converted into cysteine and excreted through urine. In this way, these vitamins protect arteries from homocysteine.  

Dietary proteins vary in the amounts of methionine they provide. Animal sources like meat, eggs, milk are abundant in it. Proteins from plant sources are more limited in it (1/3 to 1/2 less of that found in animal sources). Fruits and vegetables contain much less, which means that eating a vegetarian diet vs. a meat/dairy diet might protect from homocysteine because there is less need by the body to convert homocysteine to methionine. From this we can also infer that diets high in meat and dairy will need more of the B vitamins to make this conversion and keep homocysteine to safe levels.

Because these vitamins are so sensitive to destruction by food processing, refining and conservation, the less processed the food is, the more it will keep its vitamins. In milling wheat into white flour, for example, 50-90% of the B 6 is lost. B 12 is only obtained from foods of animal origin. The small amount required (3 micrograms) is easily supplied in most diets. This means that strict vegetarians can suffer from B 12 deficiencies. Elderly people because of inflammation of the stomach can have problems absorbing it.

The process by which homocysteine causes arteriosclerosis is as follows: In the liver, methionine, obtained from the breakdown of proteins is continually converted to homocysteine and back to methionine. This process is known as remethylation and it is dependent on vitamin B 12 and folic acid. Deficiencies of these vitamins will lead to the build up of homocysteine.

A second process, transulfuration, converts homocysteine to cystathionine, cysteine, etc for excretion in the urine. It requires B 6. Deficiency of B 6 leads to buildup of homocysteine because the body has no other way to eliminate excess homocysteine by excretion in the urine. Vitamins B 6, B 12 and folic acid need to be obtained from the diet because they are not made in the body. The homocysteine theory attributes the origin of the disease to the inadequate dietary intake of vitamin B 6 and folic acid and the subsequent failure to prevent the damage to arteries caused by elevated blood levels of homocysteine.

Consequently, populations that consume food of animal origin abundant in methionine and highly processed foods depleted of key vitamins are at higher risk for arteriosclerosis.

Other factors such as advanced age, elevated blood cholesterol, male gender, menopause, diabetes, kidney failure, thyroid deficiency, hypertension, etc – play a role too:

Homocysteine and aging

One of the strongest risk factors for arteriosclerosis is aging, especially the 7th, 8th and 9th decades. The aging process affects the ability of the body to dispose of excess homocysteine, therefore it causes an increase in homocysteine in this age range. There is also a parallel increase in cholesterol at this age, peaking at 70-80 and declining after that.

What is more, as one ages, the ability to consume food and burn calories gradually declines, and the decrease in levels of vitamin B 6 is significant. Supplementation with this vitamin is partially effective, suggesting that absorption of the B vitamins is also affected by the aging process. This is the reason why many health professionals recommend B 12 shots.

Dr. Edward Group, in his article ‘Does the vitamin B 12 shot have side effects?’ asserts: “Those who cannot digest or absorb B 12 as a result of inherited genetics or damage to the stomach and small intestine require more than can be absorbed from sublingual supplementation. In situations where a high dose is needed, or where injection is the only option, the B 12 shot is used. In some cases, B 12 shots are used as an energy booster, since B 12 plays a critical role in cellular energy production…the doctor or healthcare professional delivers the shot directly into muscle, usually into the thigh or upper arm, for easy absorption into the bloodstream.” (2)

Homocysteine and elevated blood cholesterol

Limiting the intake of animal foods high in methionine and increasing the intake of B vitamins can help lower homocysteine and cholesterol, how is this so? Experiments with animals have shown that homocysteine in its reactive tiolactone form, is capable of increasing the formation of fats in the form of triglycerides and cholesterol as low density lipoprotein (LDL) in the liver. 

Processed fats and sugars are examples of highly processed foods with no vitamins, minerals or proteins. A diet high in both will lead to a deficiency in the B vitamins that keep homocysteine low and exacerbate the tendency of blood cholesterol and lipoprotein. On the other hand, a diet high on protein of plant origin, high in B vitamins and raw foods will lower it.

The male gender, menopause and hormones

The difference between men and women when it comes to coronary heart disease is men typically are affected in the 5th and 6th decade while women are affected on the 6th decade, after menopause. Studies have consistently shown that women have slightly lower levels of homocysteine in the blood than men. After menopause, however, these levels are similar to those of men of the same age. In the eighth and ninth decades of life, the levels of homocysteine increase in both sexes.

The author believes the higher levels of estrogen in women protect them from heart disease, while the administration of synthetic estrogens and contraceptives has been shown to increase homocysteine and have a subsequent increase in blood clots and arteriosclerotic plaques. This risk in even greater in smokers who take  hormones. The reason for this is that these hormones oppose the functions of B 6 in the body, requiring higher levels of this vitamin to correct the imbalance. Cigarette smoke also antagonizes B 6 in its vital functions in the body.

Diabetes and kidney failure

Diabetes mellitus is a very common condition that predisposes affected people to rapidly advancing arteriosclerosis. Sufferers are frequently affected by heart attack, stroke, kidney failure, blindness and gangrene of the toes and feet. Diabetes is marked by the insufficient production of insulin by the pancreas or the inability of insulin to transport blood sugar into cells for production of energy. As a result, all cells in the body become starved for sugar and switch into starvation mode of cellular activity. The excess blood sugar in diabetics reacts chemically with the hemoglobin of red blood cells and with the membranes around small blood vessels and capillaries, narrowing the lumen and interfering with the passage of red blood cells. In the kidney, the clogging of small arteries gradually leads to failure of kidney function. A very striking effect of kidney failure is a remarkable buildup of homocysteine in the blood. This subjects all arteries of the body to damage and rapidly progressive arteriosclerosis.

Dialysis causes a temporary drop in homocysteine levels, but after 1-2 days the blood homocysteine returns to its elevated level. Large doses of vitamin folic acid therapy (5 milligrams per day) partially decreases the levels of homocysteine. Supplementation with B 12 or B 6 does not reduce it any further.

Homocysteine and thyroid hormone

Deficiency of thyroid hormone secretion has been known to predispose to arteriosclerosis and heart disease. In a serious deficiency case, the ability of the cells to use oxygen is impaired, the basal metabolic rate is slowed and the liver begins to make increased amounts of cholesterol and triglycerides, which increases the risk for heart disease. Administration of potent thyroid hormone like thyroxine increases this risk. Insufficient dietary iodine can increase the levels of homocysteine. In cases of hyperthyroidism, on the contrary, the levels of homocysteine are lower than in normal values.

The scientific evidence for the homocysteine theory

Dr. McCully performed his own experiments on animals to simulate what he found in children with the disease. The results showed that just after three weeks of injecting homocysteine in the animals, early arteriosclerotic plaques were found in the coronary arteries. If the animals were fed cholesterol and injected homocysteine, the arteriosclerotic plaques were found to contain fat deposits too. If the animals were given a diet deficient in B 6 and injected with homocysteine, the plaques became more prominent and widespread.

With these experiments, he successfully reproduced the cases of homocysteine he found in children with the disease. When the results were presented in a national meeting, he was met with total silence. The response to what he thought was an extraordinary finding confirming his theory about the arteriosclerotic effect of an amino acid, was very disappointing. Investigators interested in the traditional approach, went back to studying cholesterol and lipoproteins and ignored his findings and some that offered to replicate his experiment, published contradictory findings, even changing the slides they sent Dr. McCully and putting pictures of a normal artery. He performed the experiment again, this time with five times more homocysteine.

In this second experiment, blood clots had formed in the veins of the legs and abdomen and went to the lungs. In the animals that were given B 6 as well as homocysteine, no blood clots had formed and the animals survived. He repeated the experiment, this time feeding the animals a high homocysteine diet rather than injecting it. When the arteries of the animals were examined, arteriosclerotic plaques were found that closely resembled those found in the children that died from the disease. Not only had he reproduced the vascular disease, he had also reproduced the complication of blood clot formation and embolism to the lungs. He also suppressed the formation of blood clots with the administration of vitamin B 6.

After publication of these findings, scientists in Japan repeated his experiments, finding the same blood clots and arteriosclerosis, also being able to reverse it with B 6. His experiments were repeated several times by different scientists around the world and the same results were found: homocysteine caused arteriosclerosis and blood clots, proving that experimental homocysteine reproduces the essential features of homocysteine observed in children with hereditary homocysteine.

Studies of cells and tissues

By growing cells in culture from the skin of children with homocystinuria, Dr. McCully  was able to answer many questions about the disease. One of the early changes in arteriosclerotic plaques is an accumulation of mucoid matrix substance of decreased solubility in areas of damage to arterial tissues. Something else he observed is that the pattern of growth in arteriosclerosis resembles the pattern of growth of cancer cells in culture. Also, he observed that homocysteine induces cells to lose control of growth processes, causing growth of muscle cells in arteriosclerotic plaques. This fact explains why children with the disease grow rapidly in childhood and have long arms, legs, fingers, toes and great stature. The liver of children with homocystinuria was found to accumulate droplets of fat within the cytoplasm. Their mitochondria became enlarged, had bizarre shapes and become aggregated with one another, affecting how cells produced energy. All these facts were found to be key to how the cells became damaged and increased the formation of fats and cholesterol in arteriosclerosis.

In addition, homocysteine was found to activate multiple blood clotting proteins and to increase formation of thromboxane (the hormone-like fatty acid derivative causing blood clots). Homocysteine was also found to increase the binding of lipoprotein (a) to fibrin, increasing blood clots.

In his research, Dr. McCully found that components of lipoprotein homocysteine aggregates are taken up by cells of the artery wall, forming foam cells. These cells degrade and store fats and cholesterol from the LDL component, releasing them gradually to form the cholesterol crystals and fatty deposits of advanced arteriosclerotic plaques. The homocysteine component is released from foam cells and affects the oxygen utilization process of adjacent arterial cells causing increased formation of damaging free radicals. This in turn causes increased growth of muscle cells, formation of mucoid matrix from the sulfur atom of homocysteine, destruction of elastin fibers, production of fibrous collagen fibers, calcium deposits and activation of blood clotting. All of these experiments and observations explain how homocysteine causes arteriosclerotic plaques.

Human studies

Many studies followed Dr. McCully’s experiments, all of which showed that elevation of blood homocysteine is a strong independent risk factor for the development of arteriosclerotic disease. The experiments revealed a three-fold increase in the risk of heart attack in a 5-year prospective study. Elevated blood homocysteine is estimated to account for at least 10% of the risk of coronary heart disease in the US population, and is estimated to be a greater risk factor than elevated blood cholesterol (22-40 fold vs. 1.2-3.1 respectively), high blood pressure (8-18 fold) and cigarette smoking (3.5 fold) in a selected group of patients with early-onset arteriosclerosis.

Another cross-sectional study showed the risk factors to be, in order of severity, male gender, age, cigarette smoking, lack of exercise, blood pressure, heart rate, blood cholesterol and triglycerides. A total of 209 published studies of the epidemiological relation between homocysteine and arteriosclerosis have been reviewed. The consensus of these studies is that elevated blood homocysteine is a strong independent risk factor for arteriosclerosis.

A detailed study of patients with angina pectoris showed the narrowing of the coronary artery by arteriosclerotic plaques correlates better with blood homocysteine than with levels of cholesterol. The same for pulmonary embolism and people with deep vein thrombosis (blood clots in the legs).

In the case of genetic transmission of homocysteine, these results have also been documented. Thankfully, since the FDA started supplementing foods with folic acid the number of babies with birth defects (neural tube defects of the brain and spine) have greatly been reduced. Recent studies have shown that these mothers have high levels of homocysteine, predisposing their babies to birth defects.

How homocysteine causes plaques. Arteriosclerosis in progress

According to Dr. McCully, “The idea that arteries in human arteriosclerosis are narrowed only by greasy deposits is simply not true for most arteries.” Only in the aorta and some large arteries, he asserts, can you find arteriosclerosis caused by deposits of fats and proteins.

According to his research, the way homocysteine causes plaques in the arteries is through  a buildup of homocysteine in the body that leads to overproduction of a highly reactive form of homocysteine known as homocysteine thiolactone. This form of homocysteine causes LDL to become aggregated.  These aggregates are released into the blood from the liver first and then taken up by macrophages of the artery wall to form foam cells of early arteriosclerotic plaques. These foam cells degrade the LDL homocysteine thiolactone aggregates and release fat and cholesterol into developing plaques. The foam cells also release homocysteine thiolactone into surrounding cells of the artery wall affecting the way cells handle oxygen. As a result, highly reactive oxygen radicals and deposits of calcium salts accumulate within cells damaging the lining cells of arteries, promoting blood clot formation and stimulating growth of arterial muscle cells, which form fibrous tissue, mucoid matrix and degenerative elastic tissue.

In later stages, the calcified plaques of fibrous tissue give the walls of the most affected arteries a tough, brittle, hardened consistency that is very difficult to cut either with scissors or a scalpel blade. This translates into loss of elasticity and hardening of the arteries.

Arteriosclerosis and blood clotting

The main changes in arteriosclerosis then are increased fibrous tissue and calcium deposits. But this is not all that happens. Dr. McCully further describes the arteriosclerotic process as the formation of blood clots accumulating in the damaged artery:

Human arteriosclerosis, he explains, is characterized by the formation of blood clots inside arteries (thrombosis). The injury to arterial cells and tissues in the early stages of arteriosclerosis triggers complex cellular and molecular interactions and a reaction by blood clotting factors and platelets that leads to the formation of fibrin, the principal components of blood clots. This reaction causes the platelets and arterial cells to release protein growth factors that stimulate growth of the muscle cells in artery walls. This injury also causes white blood cells to adhere to the site of injury forming more foam cells and releasing more growth factors and other cell-signaling molecules called cytokines. The result of these complex interactions is increased growth of the muscle cells of the artery wall, production of fibrous tissue and ground substance, including cholesterol, inside the place of injury in the artery.

During the progression of plaques, these clots that form in damaged areas of the arterial lining contribute to the narrowing of the artery lumen. Small blood clots that stick to the surface of the plaques gradually become incorporated into the plaque increasing its thickness. In advanced arteriosclerosis, blood clots, cholesterol and fats, fibrosis and calcium salts form complicated arteriosclerotic plaques. If this process is gradual and progressive other organs and vital functions will be affected over long periods of time. Amount of blood flow to the extremities can be compromised causing gangrene.

A similar progression of advanced arteriosclerosis commonly affects the arteries leading to the brain, heart and kidneys causing them to slowly fail. A more dramatic scenario is when a blood clot occurs in an artery that is already narrowed by plaques. In the coronary artery, this will deprive a part of the heart muscle of blood flow, causing death of that part of the heart and causing a heart attack (acute myocardial infarction). When the carotid artery to the brain is affected a stroke is the end result.

Nutritional deficiencies and arteriosclerosis

Dr. McCully further stated that over consumption of fats and cholesterol has not been proven to cause arteriosclerosis. Only oxycholesterols (a trace or contaminant associated with fat), he says is actually capable of initiating arteriosclerotic plaques. The medical community has never considered the vitamin deficiency theory (B 6, B 12 and folic acid) he proposes as possible cause for arteriosclerosis. But he thinks the overconsumption of fats, sugars and highly processed foods depleted of these vitamins, could be the single cause behind the nutritional deficiencies of these water-soluble easily destroyed vitamins.

Prevention of arteriosclerotic heart disease and the homocysteine theory

Is there proof that lowering homocysteine decreases the risk of heart disease? When Dr. McCully was doing his research, there was no information regarding this in the medical literature nor funding for trial of this kind. Government funding agencies repeatedly ignored proposals for a large scale trial of the homocysteine theory. The first piece of evidence came from the study of children with homocystinuria, who after being treated with B vitamins, showed a significant decrease in the risk of blood clots. Similarly, in 1962 Dr. John Ellis proved that high doses of B 6 given to patients with carpal tunnel syndrome reduced their risk of heart attack or chest pain by 75%.

Arteriosclerosis and the homocysteine theory

The homocysteine theory proves arteriosclerosis is caused by a toxic effect of a by-product of protein breakdown. Fats and sugars are understood to contribute because of the loss of B 6 and folic acid through processing, refining and preservation of foods, creating an imbalance between the abundant methionine from foods of animal origin and the amount of these vitamins needed to keep homocysteine from building up. In homocysteine there is a deposition of fats and cholesterol that damage the artery walls by interfering in normal oxygen processing and accumulation of free radicals. Unsaturated fish oils, together with B 6, B 12, folic acid, riboflavin, choline and troxerutin (an antioxidant of plant origin) decrease both homocysteine and LDL levels.

The homocysteine theory offers explanations for arteriosclerosis that are hard to answer with the cholesterol theory. The low incidence of arteriosclerosis in Eskimos despite the high intake of fat and cholesterol is explained by the high intake of unsaturated fatty acids and B6 from fish oil.

Concluding, Dr. McCully proved that homocysteine has a direct effect on arteriosclerosis by damaging the cells of the artery walls. High dietary intake of protein, specifically methionine, and low intake of the B vitamins cause an accumulation of homocysteine leading to arteriosclerosis.


(1) http://www.stress.org/about/whos-who/fellows/m-fellows/kilmer-s-mccully-md/

(2)  http://www.globalhealingcenter.com/natural-health/vitamin-b12-shot-side-effects/